Arylindenopyridines and related therapeutic and prophylactic methods

ABSTRACT

This invention provides novel arylindenopyridines of the formula:  
                 
and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by reducing PDE activity in appropriate cells. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) ofprovisional application Ser. No. 60/284,465, filed on Apr. 18, 2001which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to novel arylindenopyridines and theirtherapeutic and prophylactic uses. Disorders treated and/or preventedusing these compounds include inflammatory and AIDS-related disorders.

BACKGROUND OF THE INVENTION

There are eleven known families of phosphodiesterases (PDE) widelydistributed in many cell types and tissues. In their nomenclature, thenumber indicating the family is followed by a capital letter thatindicates a distinct gene. A PDE inhibitor increases the concentrationof cAMP in tissue cells, and hence, is useful in the prophylaxis ortreatment of various diseases caused by the decrease in cAMP level whichis induced by the abnormal metabolism of cAMP. These diseases includeconditions such as hypersensitivity, allergy, arthritis, asthma, beesting, animal bite, bronchospasm, dysmenorrhea, esophageal spasm,glaucoma, premature labor, a urinary tract disorder, inflammatory boweldisease, stroke, erectile dysfunction, HIV/AIDS, cardiovascular disease,gastrointestinal motility disorder, and psoriasis.

Among known phosphodiesterases today, PDE1 family are activated bycalcium-calmodulin; its members include PDE1A and PDE1B, whichpreferentially hydrolyze cGMP, and PDE1C which exhibits a high affinityfor both cAMP and cGMP. PDE2 family is characterized as beingspecifically stimulated by cGMP. PDE2A is specifically inhibited byerythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). Enzymes in the PDE3 family(e.g. PDE3A, PDE3B) are specifically inhibited by cGMP. PDE4 (e.g.PDE4A, PDE4B, PDE4C, PDE4D) is a cAMP specific PDE present in T-cells,which is involved in inflammatory responses. A PDE3 and/or PDE4inhibitor would be predicted to have utility in the following disorders:autoimmune disorders (e.g. arthritis), inflammatory bowel disease,bronchial disorders (e.g. asthma), HIV/AIDS, and psoriasis. A PDE5 (e.g.PDE5A) inhibitor would be useful for the treatment of the followingdisorders: cardiovascular disease and erectile dysfunction. Thephotoreceptor PDE6 (e.g. PDE6A, PDE6B, PDE6C) enzymes specificallyhydrolyze cGMP. PDE8 family exhibits high affinity for hydrolysis ofboth cAMP and cGMP but relatively low sensitivity to enzyme inhibitorsspecific for other PDE families.

Phosphodiesterase 7 (PDE7A, PDE7B) is a cyclic nucleotidephosphodiesterase that is specific for cyclic adenosine monophosphate(cAMP). PDE7 catalyzes the conversion of cAMP to adenosine monophosphate(AMP) by hydrolyzing the 3′-phosphodiester bond of cAMP. By regulatingthis conversion, PDE7 allows for non-uniform intracellular distributionof cAMP and thus controls the activation of distinct kinase signallingpathways. PDE7A is primarily expressed in T-cells, and it has been shownthat induction of PDE7A is required for T-cell activation (Li, L.; Yee,C.; Beavo, J. A. Science 1999, 283, 848). Since PDE7A activation isnecessary for T-cell activation, small molecule inhibitors of PDE7 wouldbe useful as immunosuppressants. An inhibitor of PDE7A would bepredicted to have immunosuppressive effects with utility in therapeuticareas such as organ transplantation, autoimmune disorders (e.g.arthritis), HIV/AIDS, inflammatory bowel disease, asthma, allergies andpsoriasis.

Few potent inhibitors of PDE7 have been reported. Most inhibitors ofother phosphodiesterases have IC₅₀'s for PDE7 in the 100 μM range.Recently, Martinez, et al. (J. Med. Chem. 2000, 43, 683) reported aseries of PDE7 inhibitors, among which the two best compounds have PDE7IC₅₀'s of 8 and 13 μM. However, these compounds were only 2-3 timesselective for PDE7 over PDE4 and PDE3.

Finally, the following compounds have been disclosed, and some of themare reported to show antimicrobial activity against strains such asPlasmodium falciparum, Candida albicans and Staphylococcus aureus(Gorlitzer, K.; Herbig, S.; Walter, R. D. Pharmazie 1997, 504):

SUMMARY OF THE INVENTION

This invention provides a compound having the structure of Formula I

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   (a) R₁ is selected from the group consisting of:        -   (i) —COR₅, wherein R₅ is selected from H, optionally            substituted C₁₋₈ straight or branched chain alkyl,            optionally substituted aryl and optionally substituted            arylalkyl;            -   wherein the substituents on the alkyl, aryl and                arylalkyl group are selected from C₁₋₈ alkoxy,                phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy,                amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and                R₂₁ are independently selected from the group consisting                of hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇                cycloalkyl, benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken                together form a heterocycle or heteroaryl;        -   (ii) COOR₆, wherein R₆ is selected from H, optionally            substituted C₁₋₈ straight or branched chain alkyl,            optionally substituted aryl and optionally substituted            arylalkyl;            -   wherein the substituents on the alkyl, aryl and                arylalkyl group are selected from C₁₋₈ alkoxy,                phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy,                amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and                R₂₁ are independently selected from the group consisting                of hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇                cycloalkyl, benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken                together form a heterocycle or heteroaryl;        -   (iii) cyano;        -   (iv) a lactone or lactam formed with R₄;        -   (v) —CONR₇R₈ wherein R₇ and R₈ are independently selected            from H, C₁₋₈ straight or branched chain alkyl, C₃₋₇            cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl,            alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and            heterocyclyl;            -   wherein the alkyl, cycloalkyl, alkoxy, acyl,                alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and                heterocyclyl groups may be substituted with carboxyl,                alkyl, aryl, substituted aryl, heterocyclyl, substituted                heterocyclyl, heteroaryl, substituted heteroaryl,                hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,                alkoxy or arylalkyl,        -   or R₇ and R₈ taken together with the nitrogen to which they            are attached form a heterocycle or heteroaryl group;    -   (b) R₂ is selected from the group consisting of optionally        substituted alkyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted heterocyclyl and        optionally substituted C₃₋₇ cycloalkyl;    -   (c) R₃ is from one to four groups independently selected from        the group consisting of:        -   (i) hydrogen, halo, C₁₋₈ straight or branched chain alkyl,            arylalkyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄            carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen,            nitro, hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, aryl,            heteroaryl, and heterocyclyl;        -   (ii) —NR₁₀R₁₁ wherein R₁₀ and R₁₁ are independently selected            from H, C₁₋₈ straight or branched chain alkyl, arylalkyl,            C₃₋₇ cycloalkyl, carboxyalkyl, aryl, heteroaryl, and            heterocyclyl or R₁₀ and R₁₁ taken together with the nitrogen            form a heteroaryl or heterocyclyl group;        -   (iii) —NR₁₂COR₁₃ wherein R₁₂ is selected from hydrogen or            alkyl and R₁₃ is selected from hydrogen, alkyl, substituted            alkyl, C₁₋₃alkoxyl, carboxyalkyl, R₃₀R₃₁N(CH₂)_(p)—,            R₃₀R₃₁NCO(CH₂)_(p)—, aryl, arylalkyl, heteroaryl and            heterocyclyl or R₁₂ and R₁₃ taken together with the carbonyl            form a carbonyl containing heterocyclyl group, wherein, R₃₀            and R₃₁ are independently selected from H, OH, alkyl, and            alkoxy, and p is an integer from 1-6,            -   wherein the alkyl group may be substituted with                carboxyl, alkyl, aryl, substituted aryl, heterocyclyl,                substituted heterocyclyl, heteroaryl, substituted                heteroaryl, hydroxamic acid, sulfonamide, sulfonyl,                hydroxy, thiol, alkoxy or arylalkyl;    -   (c) R₄ is selected from the group consisting of (i)        hydrogen, (ii) C₁₋₃ straight or branched chain alkyl, (iii)        benzyl and (iv)-NR₁₃R₁₄, wherein R₁₃ and R₁₄ are independently        selected from hydrogen and C₁₋₆ alkyl;        -   wherein the C₁₋₃alkyl and benzyl groups are optionally            substituted with one or more groups selected from C₃₋₇            cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy,            trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro,            hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, amino, NR₁₃R₁₄,            aryl and heteroaryl; and    -   (e) X is selected from S and O;    -   with the proviso that when R₄ is isopropyl, then R₃ is not        halogen.

In an alternative embodiment, the invention is directed to compounds ofFormula I wherein R₁, R₃ and R₄ are as described above and R₂ is—NR₁₅R₁₆ wherein R₁₅ and R₁₆ are independently selected from hydrogen,optionally substituted C₁₋₈ straight or branched chain alkyl, arylalkyl,C₃₋₇ cycloalkyl, aryl, heteroaryl, and heterocyclyl or R₁₅ and R₁₆ takentogether with the nitrogen form a heteroaryl or heterocyclyl group; withthe proviso that when R₂ is NHR₁₆, R₁ is not —COOR₆ where R₆ is ethyl.

This invention also provides a pharmaceutical composition comprising theinstant compound and a pharmaceutically acceptable carrier.

This invention further provides a method of treating a subject having adisorder ameliorated by reducing PDE activity in appropriate cells,which comprises administering to the subject a therapeutically effectivedose of the instant pharmaceutical composition.

Finally, this invention provides a method of preventing a disorderameliorated by reducing PDE activity in appropriate cells in a subject,comprising administering to the subject a prophylactically effectivedose of the compound of claim 1 either preceding or subsequent to anevent anticipated to cause a disorder ameliorated by reducing PDEactivity in appropriate cells in the subject.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of Formula I are potent small molecule phosphodiesteraseinhibitors that have demonstrated potency for inhibition of PDE7, PDE5,and PDE4. Some of the compounds of this invention are potent smallmolecule PDE7 inhibitors which have also demonstrated good selectivityagainst PDE5 and PDE4.

Preferred embodiments for R₁ are COOR₆, wherein R₆ is selected from H,optionally substituted C₁₋₈ straight or branched chain alkyl, optionallysubstituted aryl and optionally substituted arylalkyl. Preferably R₆ isH, or C₁₋₈ straight or branched chain alkyl which may be optionallysubstituted with a substituent selected from CN and hydroxy.

Preferred embodiments for R₂ are optionally substituted aryl andoptionally substituted heteroaryl. Preferred substituents are from oneto three members selected from the group consisting of halogen, alkyl,alkoxy, alkoxyphenyl, halo, triflouromethyl, trifluoro ordifluoromethoxy, amino, alkylamino, hydroxy, cyano, and nitro.Preferably, R₂ is optionally substituted phenyl or napthyl or R₂ is

optionally substituted with from one to three members selected from thegroup consisting of halogen, alkyl, hydroxy, cyano, and nitro. Inanother embodiment of the instant compound, R₂ is —NR₁₅R₁₆.

Preferred substituents for R₃ include:

-   -   (i) hydrogen, halo, C₁₋₈ straight or branched chain alkyl, C₁₋₈        alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈        alkylsulfonyl, halogen, nitro, and hydroxy;    -   (ii) —NR₁₀R₁₁ wherein R₁₀ and R₁₁ are independently selected        from H, C₁₋₈ straight or branched chain alkyl, arylC₁₋₈alkyl,        C₃₋₇ cycloalkyl, carboxyC₁₋₈alkyl, aryl, heteroaryl, and        heterocyclyl or R₁₀ and R₁₁ taken together with the nitrogen        form a heteroaryl or heterocyclyl group;    -   (iii) —NR₁₂COR₁₃ wherein R₁₂ is selected from hydrogen or alkyl        and R₁₃ is selected from hydrogen, alkyl, substituted alkyl,        C₁₋₃alkoxyl, carboxyC₁₋₈alkyl, aryl, arylalkyl, R₃₀R₃₁N        (CH₂)_(p)—, R₃₀R₃₁NCO(CH₂)_(p)—, heteroaryl and heterocyclyl or        R₁₂ and R₁₃ taken together with the carbonyl form a carbonyl        containing heterocyclyl group, wherein, R₃₀ and R₃, are        independently selected from H, OH, alkyl, and alkoxy, and p is        an integer from 1-6.        Particularly, R₃ is selected from the group consisting of

Preferred embodiments for R₄ include hydrogen, C₁₋₃ straight or branchedchain alkyl, particularly methyl, and amino.

In a further embodiment of the instant compound, R₁ is COOR₆ and R₂ isselected from the group consisting of substituted phenyl, andsubstituted naphthyl or R₂ is NR₁₅R₁₆.

More particularly, R₁ is COOR₆ where R₆ is alkyl, R₂ is substitutedphenyl or naphthyl or R₂ is NR₁₅R₁₆, and R₃ is selected from the groupconsisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moietyof the formulae:

alkyl(CO)NH—, and R₄ is selected from hydrogen, C₁₋₃ straight orbranched chain alkyl, particularly methyl, and amino.

In a preferred embodiment, the compound is selected from the group ofcompounds shown in Table 1 hereinafter.

More preferably, the compound is selected from the following compounds:

5H-indeno[1,2-b]pyridine-3-carboxylic acid,2-amino-4-(1,3-benzodioxol-5-yl)-5-oxo-, ethyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,7-amino-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,8-(acetylamino)-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,2-methyl-4-(3-methylphenyl)-5-oxo-, methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,7-amino-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,7-amino-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-, methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-8-nitro-5-oxo-, methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,7,8-dichloro-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methylester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,7-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,8-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,8-[(3-carboxy-1-oxopropyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-,methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,8-[(3-carboxy-1-oxopropyl)amino]-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-,methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,4-(3,5-dimethylphenyl)-8-[[4-(hydroxyamino)-1,4-dioxobutyl]amino]-2-methyl-5-oxo-,methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)amino]acetyl]amino]-2-methyl-5-oxo-,methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,8-[(4-carboxy-1-oxobutyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-,methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)methylamino]acetyl]amino]-2-methyl-5-oxo-,methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,4-(3,5-dimethylphenyl)-2-methyl-8-[(4-morpholinylacetyl)amino]-5-oxo-,methyl ester

5H-indeno[1,2-b]pyridine-3-carboxylic acid,4-(3,5-dimethylphenyl)-2-methyl-5-oxo-8-[(1-piperazinylacetyl)amino]-,methyl ester

The instant compounds can be isolated and used as free bases. They canalso be isolated and used as pharmaceutically acceptable salts. Examplesof such salts include hydrobromic, hydroiodic, hydrochloric, perchloric,sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, palmoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic andsaccharic.

This invention also provides a pharmaceutical composition comprising theinstant compound and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers are well known to those skilled inthe art and include, but are not limited to, from about 0.01 to about0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Suchpharmaceutically acceptable carriers can be aqueous or non-aqueoussolutions, suspensions and emulsions. Examples of non-aqueous solventsare propylene glycol, polyethylene glycol, vegetable oils such as oliveoil, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, ethanol, alcoholic/aqueous solutions, glycerol,emulsions or suspensions, including saline and buffered media. Oralcarriers can be elixirs, syrups, capsules, tablets and the like. Thetypical solid carrier is an inert substance such as lactose, starch,glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate,mannitol and the like. Parenteral carriers include sodium chloridesolution, Ringer's dextrose, dextrose and sodium chloride, lactatedRinger's and fixed oils. Intravenous carriers include fluid and nutrientreplenishers, electrolyte replenishers such as those based on Ringer'sdextrose and the like. Preservatives and other additives can also bepresent, such as, for example, antimicrobials, antioxidants, chelatingagents, inert gases and the like. All carriers can be mixed as neededwith disintegrants, diluents, granulating agents, lubricants, bindersand the like using conventional techniques known in the art.

This invention further provides a method of treating a subject having acondition ameliorated by reducing PDE activity in appropriate cells,which comprises administering to the subject a therapeutically effectivedose of the instant pharmaceutical composition.

In one embodiment, the disorder is an inflammatory disorder. In anotherembodiment, the disorder is an AIDS-related disorder. Examples ofdisorders treatable by the instant pharmaceutical composition include,without limitation, organ transplantation, autoimmune disorders (e.g.arthritis), immune challenge such as a bee sting, inflammatory boweldisease, bronchial disorders (e.g. asthma), HIV/AIDS, cardiovasculardisorder, erectile dysfunction, allergies, and psoriasis. In thepreferred embodiment, the disorder is rheumatoid arthritis.

As used herein, the term “subject” includes, without limitation, anyanimal or artificially modified animal having a disorder ameliorated byreducing PDE activity in appropriate cells. In a preferred embodiment,the subject is a human. In a more preferred embodiment, the subject is ahuman.

As used herein, “appropriate cells” include, by way of example, cellswhich display PDE activity. Specific examples of appropriate cellsinclude, without limitation, T-lymphocytes, muscle cells, neuro cells,adipose tissue cells, monocytes, macrophages, fibroblasts.

Administering the instant pharmaceutical composition can be effected orperformed using any of the various methods known to those skilled in theart. The instant compounds can be administered, for example,intravenously, intramuscularly, orally and subcutaneously. In thepreferred embodiment, the instant pharmaceutical composition isadministered orally. Additionally, administration can comprise givingthe subject a plurality of dosages over a suitable period of time. Suchadministration regimens can be determined according to routine methods.

As used herein, a “therapeutically effective dose” of a pharmaceuticalcomposition is an amount sufficient to stop, reverse or reduce theprogression of a disorder. A “prophylactically effective dose” of apharmaceutical composition is an amount sufficient to prevent adisorder, i.e., eliminate, ameliorate and/or delay the disorder's onset.Methods are known in the art for determining therapeutically andprophylactically effective doses for the instant pharmaceuticalcomposition. The effective dose for administering the pharmaceuticalcomposition to a human, for example, can be determined mathematicallyfrom the results of animal studies.

In one embodiment, the therapeutically and/or prophylactically effectivedose is a dose sufficient to deliver from about 0.001 mg/kg of bodyweight to about 200 mg/kg of body weight of the instant pharmaceuticalcomposition. In another embodiment, the therapeutically and/orprophylactically effective dose is a dose sufficient to deliver fromabout 0.05 mg/kg of body weight to about 50 mg/kg of body weight. Morespecifically, in one embodiment, oral doses range from about 0.05 mg/kgto about 100 mg/kg daily. In another embodiment, oral doses range fromabout 0.05 mg/kg to about 50 mg/kg daily, and in a further embodiment,from about 0.05 mg/kg to about 20 mg/kg daily. In yet anotherembodiment, infusion doses range from about 1.0 μg/kg/min to about 10mg/kg/min of inhibitor, admixed with a pharmaceutical carrier over aperiod ranging from about several minutes to about several days. In afurther embodiment, for topical administration, the instant compound canbe combined with a pharmaceutical carrier at a drug/carrier ratio offrom about 0.001 to about 0.1.

This invention still further provides a method of preventing aninflammatory response in a subject, comprising administering to thesubject a prophylactically effective amount of the instantpharmaceutical composition either preceding or subsequent to an eventanticipated to cause the inflammatory response in the subject. In thepreferred embodiment, the event is an insect sting or an animal bite.

Definitions and Nomenclature

Unless otherwise noted, under standard nomenclature used throughout thisdisclosure the terminal portion of the designated side chain isdescribed first, followed by the adjacent functionality toward the pointof attachment.

As used herein, the following chemical terms shall have the meanings asset forth in the following paragraphs: “independently”, when inreference to chemical substituents, shall mean that when more than onesubstituent exists, the substituents may be the same or different.

“Alkyl” shall mean straight, cyclic and branched-chain alkyl. Unlessotherwise stated, the alkyl group will contain 1-20 carbon atoms. Unlessotherwise stated, the alkyl group may be optionally substituted with oneor more groups such as halogen, OH, CN, mercapto, nitro, amino,C₁-C₈-alkyl, C₁-C₈-alkoxyl, C₁-C₈-alkylthio, C₁-C₈-alkyl-amino,di(C₁-C₈-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl,carboxy, alkoxycarbonyl, C₁-C₈-alkyl-CO—O—, C₁-C₈-alkyl-CO—NH—,carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl,aryl(c₁-C₈)alkyl, heterocyclyl, and heteroaryl.

“Alkoxy” shall mean —O-alkyl and unless otherwise stated, it will have1-8 carbon atoms.

“Halogen” shall mean fluorine, chlorine, bromine or iodine; “PH” or “Ph”shall mean phenyl; “Ac” shall mean acyl; “Bn” shall mean benzyl.

The term “acyl” as used herein, whether used alone or as part of asubstituent group, means an organic radical having 2 to 6 carbon atoms(branched or straight chain) derived from an organic acid by removal ofthe hydroxyl group. The term “Ac” as used herein, whether used alone oras part of a substituent group, means acetyl.

“Aryl” or “Ar,” whether used alone or as part of a substituent group, isa carbocyclic aromatic radical including, but not limited to, phenyl, 1-or 2-naphthyl and the like. The carbocyclic aromatic radical may besubstituted by independent replacement of 1 to 5 of the hydrogen atomsthereon with halogen, OH, CN, mercapto, nitro, amino, C₁-C₈-alkyl,C₁-C₈-alkoxyl, C₁-C₈-alkylthio, C₁-C₈-alkyl-amino, di(C₁-C₈-alkyl)amino,(mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy,alkoxycarbonyl, C₁-C₈-alkyl-CO—O—, C₁-C₈-alkyl-CO—NH—, or carboxamide.Illustrative aryl radicals include, for example, phenyl, naphthyl,biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl,carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl,hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl,acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. “Ph”or “PH” denotes phenyl.

Whether used alone or as part of a substituent group, “heteroaryl”refers to a cyclic, fully unsaturated radical having from five to tenring atoms of which one ring atom is selected from S, O, and N; 0-2 ringatoms are additional heteroatoms independently selected from S, O, andN; and the remaining ring atoms are carbon. The radical may be joined tothe rest of the molecule via any of the ring atoms. Exemplary heteroarylgroups include, for example, pyridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl,furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, 2-oxazepinyl,azepinyl, N-oxo-pyridyl, 1-dioxothienyl, benzothiazolyl, benzoxazolyl,benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl,benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl,benzothiopyranyl, indazolyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl,furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, orfuro[2,3-b]pyridinyl), imidazopyridinyl (such as imidazo[4,5-b]pyridinylor imidazo[4,5-c]pyridinyl), naphthyridinyl, phthalazinyl, purinyl,pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, thienothienyl,and furyl. The heteroaryl group may be substituted by independentreplacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH,CN, mercapto, nitro, amino, C₁-C₈-alkyl, C₁-C₈-alkoxyl, C₁-C₈-alkylthio,C₁-C₈-alkyl-amino, di(C₁-C₈-alkyl)amino, (mono-, di-, tri-, and per-)halo-alkyl, formyl, carboxy, alkoxycarbonyl, C₁-C₈-alkyl-CO—O—,C₁-C₈-alkyl-CO—NH—, or carboxamide. Heteroaryl may be substituted with amono-oxo to give for example a 4-oxo-1H-quinoline.

The terms “heterocycle,” “heterocyclic,” and “heterocyclo” refer to anoptionally substituted, fully or partially saturated cyclic group whichis, for example, a 4- to 7-membered monocyclic, 7- to 11-memberedbicyclic, or 10- to 15-membered tricyclic ring system, which has atleast one heteroatom in at least one carbon atom containing ring. Eachring of the heterocyclic group containing a heteroatom may have 1, 2, or3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfuratoms, where the nitrogen and sulfur heteroatoms may also optionally beoxidized. The nitrogen atoms may optionally be quaternized. Theheterocyclic group may be attached at any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl;pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl;isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl;piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl;2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl;tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl;thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone;1,3-dioxolane; dioxanyl; thietanyl; thiiranyl; and the like. Exemplarybicyclic heterocyclic groups include quinuclidinyl;tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl;dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone;dihydrobenzopyranyl; indolinyl; isochromanyl; isoindolinyl; piperonyl;tetrahydroquinolinyl; and the like.

Substituted aryl, substituted heteroaryl, and substituted heterocyclemay also be substituted with a second substituted-aryl, a secondsubstituted-heteroaryl, or a second substituted-heterocycle to give, forexample, a 4-pyrazol-1-yl-phenyl or 4-pyridin-2-yl-phenyl.

Designated numbers of carbon atoms (e.g., C₁₋₈) shall referindependently to the number of carbon atoms in an alkyl or cycloalkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

Unless specified otherwise, it is intended that the definition of anysubstituent or variable at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. It isunderstood that substituents and substitution patterns on the compoundsof this invention can be selected by one of ordinary skill in the art toprovide compounds that are chemically stable and that can be readilysynthesized by techniques known in the art as well as those methods setforth herein.

Where the compounds according to this invention have at least onestereogenic center, they may accordingly exist as enantiomers. Where thecompounds possess two or more stereogenic centers, they may additionallyexist as diastereomers. Furthermore, some of the crystalline forms forthe compounds may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compoundsmay form solvates with water (i.e., hydrates) or common organicsolvents, and such solvates are also intended to be encompassed withinthe scope of this invention.

Some of the compounds of the present invention may have trans and cisisomers. In addition, where the processes for the preparation of thecompounds according to the invention give rise to mixture ofstereoisomers, these isomers may be separated by conventional techniquessuch as preparative chromatography. The compounds may be prepared as asingle stereoisomer or in racemic form as a mixture of some possiblestereoisomers. The non-racemic forms may be obtained by either synthesisor resolution. The compounds may, for example, be resolved into theircomponents enantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation. The compounds may also beresolved by covalent linkage to a chiral auxiliary, followed bychromatographic separation and/or crystallographic separation, andremoval of the chiral auxiliary. Alternatively, the compounds may beresolved using chiral chromatography.

This invention will be better understood by reference to theExperimental Details which follow, but those skilled in the art willreadily appreciate that these are only illustrative of the invention asdescribed more fully in the claims which follow thereafter.Additionally, throughout this application, various publications arecited. The disclosure of these publications is hereby incorporated byreference into this application to describe more fully the state of theart to which this invention pertains.

Experimental Details

I. General Synthetic Schemes

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below andillustrated in the following general schemes. The products of someschemes can be used as intermediates to produce more than one of theinstant compounds. The choice of intermediates to be used to producesubsequent compounds of the present invention is a matter of discretionthat is well within the capabilities of those skilled in the art.

Procedures described in Scheme 1, wherein R_(3a), R_(3b), R_(3c), andR_(3d) are independently any R₃ group, and R₁, R₂, R₃, and R₄ are asdescribed above, can be used to prepare compounds of the inventionwherein X is O.

Benzylidenes 2 may be obtained by known methods (Bullington, J. L;Cameron, J. C.; Davis, J. E.; Dodd, J. H.; Harris, C. A.; Henry, J. R.;Pellegrino-Gensey, J. L.; Rupert, K. C.; Siekierka, J. J. Bioorg. Med.Chem. Lett. 1998, 8, 2489; Petrow, V.; Saper, J.; Sturgeon, B. J. Chem.Soc. 1949, 2134). Hantzsch reaction of the benzylidene compounds withenamines 3 can be performed in refluxing acetic acid (Petrow et al.,supra). When the desired enamines are not available, alternate Hantzschconditions may be utilized which involve adding ammonium acetate to thereaction. The resulting dihydropyridines 4 are oxidized with chromiumtrioxide to obtain the desired pyridines 1 (Petrow et al., supra). Incases where the substitution pattern on the fused aromatic ring (R₃)leads to a mixture of regioisomers, the products can be separated bycolumn chromatography.

In some cases, especially where R₂ is an alkyl group, anothermodification of the Hantzsch may be performed which uses threecomponents (Bocker, R. H.; Buengerich, P. J. Med. Chem. 1986, 29, 1596).Where R₂ is an alkyl group it is also necessary to perform the oxidationwith DDQ or MnO₂ instead of chromium (VI) oxide (Vanden Eynde, J. J.;Delfosse, F.; Mayence, A.; Van Haverbeke, Y. Tetrahedron 1995, 51,6511).

In order to obtain the corresponding carboxylic acids and amides, thecyanoethyl esters 5 are prepared as described above. The esters areconverted to the carboxylic acids by treatment with sodium hydroxide inacetone and water (Ogawa, T.; Matsumoto, K.; Yokoo, C.; Hatayama, K.;Kitamura, K. J. Chem. Soc., Perkin Trans. 1 1993, 525). Thecorresponding amides can then be obtained from the acids using standardmeans.

The procedure for making compounds where R₄ is NH₂ may be slightlymodified. These compounds are prepared in one step from the benzylidenes2 and alkyl amidinoacetate (Kobayashi, T.; Inoue, T.; Kita, Z.; Yoshiya,H.; Nishino, S.; Oizumi, K.; Kimura, T. Chem. Pharm. Bull. 1995, 43,788) as depicted in Scheme 4 wherein R is R₅ or R₆ as described above.

The dihydropyridine lactones 9 can be synthesized from benzylidenes 8(Zimmer, H.; Hillstrom, W. W.; Schmidt, J. C.; Seemuth, P. D.; Vogeli,R. J. Org. Chem. 1978, 43, 1541) and 1,3-indanedione, as shown in Scheme5, and the corresponding pyridine is then obtained by oxidation withmanganese dioxide.

Representative schemes to modify substituents on the fused aromatic ringare shown below. The amines 11 are obtained from the corresponding nitrocompounds 10 by reduction with tin (II) chloride (Scheme 6). Reaction ofthe amines with acetyl chloride provide the amides 12.

In accordance with Scheme 7 wherein Y is O, and n is an integer from1-3, an alkyl chain with a carboxylic acid at the terminal end can alsobe added to the amines 11. For example, reaction with either succinicanhydride (Omuaru, V. O. T.; Indian J. Chem., Sect B. 1998, 37, 814) orβ-propiolactone (Bradley, G.; Clark, J.; Kernick, W. J. Chem. Soc.,Perkin Trans. 1 1972, 2019) can provide the corresponding carboxylicacids 13. These carboxylic acids are then converted to the hydroxamicacids 14 by treatment with ethyl chloroformate and hydroxylamine (Reddy,A. S.; Kumar, M. S.; Reddy, G. R. Tetrahedron Lett. 2000, 41, 6285).

The amines 11 can also be treated with glycolic acid to afford alcohols15 (Jursic, B. S.; Zdravkovski, Z. Synthetic Comm. 1993, 23, 2761) asshown in Scheme 8.

As shown in Scheme 9, the aminoindenopyridines 11 may also be treatedwith chloroacetylchloride followed by amines to provide the moreelaborate amines 16 (Weissman, S. A.; Lewis, S.; Askin, D.; Volante, R.P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 7459). Where R₆ is ahydroxyethyl group, the compounds can be further converted topiperazinones 17.

The 4-aminoindenopyridines 18 can be synthesized from the4-chloroindenopyridines 19 using a known procedure (Gorlitzer, K.;Herbig, S.; Walter, R. D. Pharmazie 1997, 504) or via palladiumcatalyzed coupling (Scheme 10).

II. Specific Compound Syntheses

Specific compounds which are representative of this invention can beprepared as per the following examples. No attempt has been made tooptimize the yields obtained in these reactions. Based on the following,however, one skilled in the art would know how to increase yieldsthrough routine variations in reaction times, temperatures, solventsand/or reagents.

The products of certain syntheses can be used as intermediates toproduce more than one of the instant compounds. In those cases, thechoice of intermediates to be used to produce compounds of the presentinvention is a matter of discretion that is well within the capabilitiesof those skilled in the art.

EXAMPLE 1 Hantzsch Condensation to Form Dihydropyridine 4 (R₁=COOMe;R₂=3,5-dimethylphenyl; R_(3b,c)=Cl; R_(3a,b)=H; R₄=Me)

To a refluxing solution of benzylidene 2 (0.500 g, 1.5 mmol) in aceticacid (10 mL) was added methyl-3-aminocrotonate (0.695 g, 6.0 mmol). Thereaction was heated to reflux for 20 minutes, then water was added untila precipitate started to form. The reaction was cooled to roomtemperature. The mixture was filtered and washed with water to obtain0.354 g (55%) of a red solid. MS m/z 450 (M⁺+23), 428 (M⁺+1).

EXAMPLE 2 Alternate Hantzsch Conditions to Form Dihydropyridine 4(R₁=CO₂Me; R₂=2,4-dimethylphenyl; R₃=H; R₄=Et)

To a refluxing solution of benzylidene 2 (1.00 g, 3.82 mmol) in aceticacid (12 Ml) was added methyl propionylacetate (1.98 g, 15.2 mmol) andammonium acetate (1.17 g, 15.2 mmol). The reaction was heated for 20 minand then cooled to room temperature. No product precipitated from thesolution, so the reaction was heated to reflux and then water was addeduntil a solid began to precipitate. After cooling to room temperature,the mixture was filtered and the red solid washed with water to yield1.29 g (90%) of product. MS m/z 396 (M⁺+23), 374 (M⁺+1).

EXAMPLE 3 Oxidation of Dihydropyridine 4 to Pyridine 1 (R₁=COOMe;R₂=3,5-dimethylphenyl; R_(3b,c)=Cl; R_(3a,d)=H; R₄=Me)

To a refluxing solution of dihydropyridine 4 (0.250 g, 0.58 mmol) inacetic acid (10 mL) was added a solution of chromium (VI) oxide (0.584g, 0.58 mmol) in 1 mL water. After 30 minutes at reflux, the reactionwas diluted with water until a precipitate started to form. The mixturewas cooled to room temperature and allowed to stand overnight. Themixture was filtered and washed with water to give 0.199 g (81%) of ayellow solid. MS m/z 448 (M⁺+23), 426 (M⁺+1).

EXAMPLE 4 Oxidation of Dihydropyridine 4 to Pyridine 1 (R₁=COOMe;R₂=(4-methyl)-1-naphthyl; R_(3b,c)=H, NO₂/NO₂, H; R=Me)

To a refluxing suspension of regioisomeric dihydropyridines 4 (3.59 g,8.16 mmol) in acetic acid (40 mL) was added a solution of chromium (VI)oxide (0.816 g, 8.16 mmol) in 3 mL water. After 20 minutes at reflux,the reaction was diluted with water until a precipitate started to form.The mixture was cooled to room temperature and allowed to standovernight. The mixture was filtered and washed with water to yield themixture of regioisomers as a yellow solid. The products were purified bycolumn chromatography eluting with hexanes:ethyl acetate to yield 1.303g (37%) of pyridine 1 (R_(3b)=NO₂; R_(3c)=H) and 0.765 g (21%) of itsregioisomer (R_(3b)=H; R_(3c)=NO₂). MS m/z 461 (M⁺+23), 439 (M⁺+1).

EXAMPLE 5 Alternate Three Component Hantzsch Reaction to FormDihydropyridine 4 (R₁=CO₂Me; R₂=cyclohexyl; R₃=H; R₄=Me)

Cyclohexane carboxaldehyde (2.0 g, 17.8 mmol), 1,3-indandione (2.6 g,17.8 mmol), methylacetoacetate (2.0 g, 17.8 mmol), and ammoniumhydroxide (1 mL) were refluxed in 8 mL of methanol for 1.5 hours. Thetemperature was lowered to approximately 50° C. and the reaction wasstirred overnight. The reaction was cooled to room temperature, filteredand the solid washed with water. The residue was then dissolved in hotethanol and filtered while hot. The filtrate was concentrated to yield4.1 g (68%) of the product which was used without purification. MS m/z336 (M-1).

EXAMPLE 6 DDQ Oxidation of Dihydropyridine 4 (R₁=CO₂Me; R₂=cyclohexyl;R₃=H; R₄=Me)

To a solution of dihydropyridine 4 (2.50 g, 7.40 mmol) in 15 mL ofdichloromethane was added 2,3-dichloro-3,6-dicyano-1,4-benzoquinone(1.70 g, 7.40 mmol). The reaction was stirred at room temperature forfour hours. The mixture was filtered and the residue was washed withdichloromethane. After the filtrate was concentrated, the residue waspurified by column chromatography eluting with ethyl acetate:hexanes toyield 0.565 g (23%) of a yellow solid. MS m/z 358 (M⁺+23), 336 (M⁺+1).

EXAMPLE 7 MnO₂ Oxidation of Dihydropyridine 4 (R₁=CO₂Me;R₂=4-(dimethylamino)phenyl; R₃=H; R₄=Me)

To a solution of dihydropyridine 4 (0.50 g, 1.3 mmol) in 10 mL ofdichloromethane was added manganese dioxide (2.5 g, 28.7 mmol). Thereaction was stirred at room temperature overnight before filtering andwashing with dichloromethane. The filtrate was concentrated to yield0.43 g (88%) of orange solid 1. MS m/z 395 (M⁺+23), 373 (M⁺+1).

EXAMPLE 8 Cleavage of Carboxylic Ester 5 (R₂=2,4-dimethylphenyl; R₃=H;R₄=Me)

To a suspension of ester 5 (2.75 g, 6.94 mmol) in acetone (50 mL) wasadded aqueous 1 M NaOH (100 mL). After stirring at room temperature for24 hours, the reaction mixture was diluted with 100 mL of water andwashed with dichloromethane (2×100 mL). The aqueous layer was cooled to0° C. and acidified with concentrated HCl. The mixture was filtered andwashed with water to yield 1.84 g (77%) yellow solid 6. MS m/z 366(M⁺+23), 343 (M⁺+1).

EXAMPLE 9 Preparation of Amide 7 (R₂=2,4-dimethylphenyl; R₃=H; R₄=Me;R₅═H; R₆=Me)

A solution of carboxylic acid 6 (0.337 g, 0.98 mmol) in thionyl chloride(10 mL) was heated at reflux for 1 hour. The solution was cooled andconcentrated in vacuo. The residue was diluted with CCl₄ andconcentrated to remove the residual thionyl chloride. The residue wasthen dissolved in THF (3.5 mL) and added to a 0° C. solution ofmethylamine (1.47 mL of 2.0 M solution in THF, 2.94 mmol) in 6.5 mL THF.The reaction was warmed to room temperature and stirred overnight. Themixture was poured into water, filtered, washed with water and dried toyield 0.263 g (75%) of tan solid. MS m/z 357 (M⁺+1).

EXAMPLE 10 Preparation of Pyridine 1 (R₁=CO₂Et; R₂=4-nitrophenyl; R₃=H;R₄═NH₂)

To a refluxing solution of benzylidene 2 (1.05 g, 3.76 mmol) in 10 mL ofacetic acid was added ethyl amidinoacetate acetic acid salt (0.720 g,3.76 mmol). The resulting solution was heated at reflux overnight. Aftercooling to room temperature, the resulting precipitate was removed byfiltration and washed with water. This impure residue was heated in aminimal amount of ethanol and then filtered to yield 0.527 g (35%) of ayellow solid. MS m/z 412 (M⁺+23), 390 (M⁺+1).

EXAMPLE 11 Hantzsch Condensation of Benzylidene 8 (R₂=3-methoxyphenyl)and 1,3-indandione)

The benzylidene 8 (2.00 g, 9.2 mmol), 1,3-indandione (1.34 g, 0.2 mmol)and ammonium acetate (2.83 g, 36.7 mmol) were added to 30 mL of ethanoland heated to reflux overnight. The reaction mixture was cooled to roomtemperature and diluted with ethanol. A yellow precipitate was collectedby filtration, washed with ethanol, and dried under vacuum to yield 1.98g (63%) of the dihydropyridine 9. MS m/z 346 (M⁺+1).

EXAMPLE 12 Reduction to Prepare Amine 11 (R₁=CO₂Me; R₂=4-methylnaphthyl;R₄=Me)

To a refluxing suspension of pyridine 10 (0.862 g, 1.97 mmol) in 35 mLof ethanol was added a solution of tin (II) chloride dihydrate (1.33 g,5.90 mmol) in 6 mL of 1:1 ethanol: concentrated HCl. The resultingsolution was heated at reflux overnight. Water was added until aprecipitate started to form and the reaction was cooled to roomtemperature. The mixture was then filtered and washed with water. Afterdrying, the residue was purified by column chromatography eluting withhexanes:ethyl acetate to yield 0.551 g (69%) of an orange solid. MS m/z431 (M⁺+23), 409 (M⁺+1).

EXAMPLE 13 Acetylation of Amine 11 (R₁=CO₂Et;R₂=3,4-methylenedioxyphenyl; R₄=Me)

To a solution of amine 11 (0.070 g, 0.174 mmol) in 15 mL ofdichloromethane was added triethylamine (0.026 g, 0.261 mmol) and acetylchloride (0.015 g, 0.192 mmol). After stirring overnight at roomtemperature, the reaction mixture was diluted with water and thenextracted with dichloromethane (3×35 mL). The combined organics werewashed with brine, dried over MgSO₄, and concentrated. The residue waspurified by silica gel chromatography eluting with hexanes:ethyl acetateto yield 0.054 g (70%) of amide 12. MS m/z 467 (M⁺+23), 445 (M⁺+1).

EXAMPLE 14 Preparation of Carboxylic Acid 13 (R₁=CO₂Me;R₂=3,5-dimethylphenyl; R₄=Me; Y=O; n=2)

To a suspension of amine 11 (0.079 g, 0.212 mmol) in 5 mL of benzene wasadded succinic anhydride (0.021 g, 0.212 mmol). After heating at refluxfor 24 hours, the reaction mixture was filtered and washed with benzene.The residue was dried under high vacuum and then washed with ether toremove the excess succinic anhydride. This yielded 0.063 g (63%) ofcarboxylic acid 13. MS m/z 473 (M⁺+1).

EXAMPLE 15 Preparation of Carboxylic Acid 13 (R₁=CO₂Me;R₂=3,5-dimethylphenyl; R₄=Me; Y═H₂; n=1)

To a refluxing solution of amine 11 (0.078 g, 0.210 mmol) in 5 mL ofacetonitrile was added β-propiolactone (0.015 g, 0.210 mmol). Thereaction was heated to reflux for 72 hours before cooling to roomtemperature. The reaction mixture was concentrated. The residue wasmixed with 10% aqueous sodium hydroxide and washed sequentially withether and ethyl acetate. The aqueous layer was acidified withconcentrated HCl and extracted with dichloromethane (2×25 mL). Thecombined organics were dried over MgSO₄, filtered, and concentrated. Theresidue was purified by column chromatography eluting with 5% MeOH indichloromethane to yield 0.020 g (21%) of an orange solid. MS m/z 467(M⁺+23), 445 (M⁺+1).

EXAMPLE 16 Preparation of Hydroxamic Acid 14 (R₁=CO₂Me;R₂=(4-methyl)-1-naphthyl; Y=O; n=2; R₄=Me)

To a 0° C. suspension of carboxylic acid 13 (0.054 g, 0.106 mmol) in 10mL of diethyl ether was added triethylamine (0.014 g, 0.138 mmol) andthen ethyl chloroformate (0.014 g, 0.127 mmol). The mixture was stirredat 0° C. for 30 minutes and them warmed to room temperature. A solutionof hydroxylamine (0.159 mmol) in methanol was added and the reaction wasstirred overnight at room temperature. The mixture was filtered and theresidue was washed with ether and dried under vacuum to yield 0.030 g(54%) of a yellow solid. MS m/z 524 (M⁺+1).

EXAMPLE 17 Preparation of Amide 15 (R₁=CO₂Me; R₂=3,5-dimethylphenyl;R₄=Me)

A mixture of amine 11 (0.201 g, 0.54 mmol) and glycolic acid (0.049 g,0.65 mmol) was heated at 120-160° C. for 30 minutes. During heating,more glycolic acid was added to ensure that excess reagent was present.Once the starting material was consumed, the reaction was cooled to roomtemperature, and diluted with dichloromethane. The resulting mixture wasextracted with 20% NaOH, followed by 10% HCl, and finally water. Thecombined organics were concentrated and triturated with ether.Purification by column chromatography eluting with ethyl acetate:hexanesyielded 0.012 g (5%) of a yellow solid. MS m/z 453 (M⁺+23), 431 (M⁺+1).

EXAMPLE 18 Preparation of Amide 16 (R₁=CO₂Me; R₂=3,5-dimethylphenyl;R₄=Me; NR₆R₇=morpholino)

To a 0° C. mixture of amine 11 (0.123 g, 0.331 mmol) in 2 mL of 20%aqueous NaHCO₃ and 3 mL of ethyl acetate was added chloroacetyl chloride(0.047 g, 0.413 mmol). The reaction was warmed to room temperature andstirred for 45 minutes. The mixture was poured into a separatory funneland the aqueous layer was removed. The organic layer containing thecrude chloroamide was used without purification. To the ethyl acetatesolution was added morpholine (0.086 g, 0.992 mmol) and the reaction washeated to approx. 65° C. overnight. The reaction was diluted with waterand cooled to room temperature. After extraction with ethyl acetate(3×25 mL), the combined organics were washed with brine, dried overMgSO₄ and concentrated to yield 0.130 g (79%) of a yellow solid. MS m/z522 (M⁺+23), 500 (M⁺+1).

EXAMPLE 19 Preparation of piperazinone 17 (R₁=CO₂Me;R₂=3,5-dimethylphenyl; R₄=Me; R₇=H)

To a 0° C. solution of amide 16 (R₆=CH₂CH₂OH) (0.093 g, 0.20 mmol), trin-butylphosphine (0.055 g, 0.27 mmol) in 0.35 mL ethyl acetate wasslowly added di-tert-butyl azodicarboxylate (0.062 g, 0.27 mmol) in 0.20mL ethyl acetate. The reaction was allowed to stand for 15 minutes andthen heated to 40° C. overnight. 4.2 M ethanolic HCl was added dropwise.The mixture was cooled to 0° C. and allowed to stand for 2 hours. Themixture was filtered and washed with cold ethyl acetate. Purification bycolumn chromatography with 1-5% MeOH in CH₂Cl₂ yielded 0.011 (12%) of awhite solid. MS m/z 478 (M⁺+23), 456 (M⁺+1).

EXAMPLE 20 Preparation of 4-Aminoindenopyridine 19 (R₁=CO₂Me; R₄=Me;R₆=Me; R₇=phenyl)

To a solution of 4-chloroindenopyridine 18 (0.069 g, 0.240 mmol) in 10mL of 2-ethoxyethanol was added N-methylaniline (0.026 g, 0.240 mmol).The reaction was heated at reflux for 96 hours. After cooling to roomtemperature, the solution was concentrated. The residue was purified bycolumn chromatography eluting with hexanes:ethyl acetate to yield 0.029g (34%) of an orange solid. MS m/z 359 (M⁺+1).

EXAMPLE 21 Preparation of 4-Aminoindenopyridine 19 (R₁=CO₂Me; R₄=Me;R₆=H; R₇=cyclopentyl) by Palladium Catalyzed Coupling

A mixture of 4-chloroindenopyridine 18 (0.100 g, 0.347 mmol),cyclopentylamine (0.035 g, 0.416 mmol), palladium (II) acetate (0.004 g,0.0017 mmol), 2-(di-t-butylphosphino)biphenyl (0.010 g, 0.0035 mmol),and cesium carbonate (0.124 g, 0.382 mmol) in 10 mL of dioxane washeated at reflux overnight. The reaction was cooled to room temperature,diluted with water, and extracted with ethyl acetate (3×35 mL). Thecombined organics were washed with brine, dried over Na₂SO₄, andconcentrated. The residue was purified by column chromatography elutingwith ethyl acetate:hexanes. The purified oil was dissolved in ether andcooled to 0° C. To this solution was slowly added 1.0 M HCl in ether.The resulting precipitate was isolated by filtration, washed with ether,and dried under vacuum to yield 0.032 g (25%) of a yellow solid. MS m/z359 (M⁺+23), 337 (M⁺+1).

Following the general synthetic procedures outlined above and inExamples 1-21, the compounds of Table 1 below were prepared. TABLE 1 Ia

MS No. R₁ R₂ R_(3a) R_(3b) R_(3c) R_(3d) R₄ (M + 1) 1 CN

H H H H Me 341 2 CO₂Et

H H H H Me 388 3 CO₂t-Bu

H H H H Me 416 4 CO₂t-Bu

H H H H Me 432 5 CO₂Et

H H H H Me 389 6 CO₂H

H H H H Me 360 7 CO₂Et

H H H H Me 480 8 CO₂Et

H H H H Me 482 9 CO₂Et

H H H H Me 424 10 CO₂H

H H H H Me 376 11 CO₂Et Ph H H H H Me 344 12 CO₂Et

H H H H Me 374 13 CO₂Et

H H H H Me 434 14 CO₂Et

H H H H Me 454 15 CO₂Bn

H H H H Me 450 16

H H H H Me 507 17 CO₂Me

H H H H Me 390 18 CO₂Me

H H H H Me 374 19 CO₂Et

H H H H Me 404 20 CO₂Et

H H H H Me 404 21 CO₂Et

H H H H Me 454 22 CO₂Et

H H H H NH₂ 411 (M + 23) 23 CO₂Et

H H H H Me 388 25 CO₂Et

H H H H NH₂ 405 26 CO₂Et

H H H H NH₂ 390 27 CO₂Et Ph H H H H NH₂ 345 28 CO₂Et

H H H H Me 402 29 CO₂Et

H H H H Me 483 30 CO₂Me Ph H H H H Me 330 31 CO₂Et

H H H H Me 402 32 CO₂Et

H NO₂ H H Me 433 33

H H H H Me 413 34 CO₂Et

H H H H Me 433 35 CO₂Et

H H NO₂ H Me 433 36 CO₂Me

H H H H Me 398 37 CO₂Et

H H NH₂ H Me 403 38 CONH₂

H H H H Me 359 39 CO₂Et

H H H H Me 372 40 CO₂Et

H NH₂ H H Me 403 41 CO₂Et

H H H H Me 334 42 CO₂Et 2-Thienyl H H H H Me 350 43 CO₂Me

H H H H Me 358 44 CO₂Me

H H H H Me 388 45 CO₂Me

H H H H Me 419 46 CO₂Me

H H H H Me 388 47 CO₂Me 4-Pyridyl H H H H Me 331 48 CO₂Me

H H H H Me 374 49 CO₂Me

H H H H Me 454 50 CO₂Me

H H H H Me 439 51 CO₂Me

H H H H Me 358 52 CO₂Et

H H H H Me 372 53 CO₂Me

H H H H Me 410 54 CO₂Me

H H H H Me 375 55 CO₂Et

H NHAc H H Me 445 56 CO₂Et

H H NHAc H Me 445 57 CO₂Et

H H H H Me 358 58 CO₂Et

H H H H Me 358 59 CO₂Et

H H H H Me 358 60 CO₂Et

H NO₂ H H Me 457 61 CO₂Et

H H NO₂ H Me 457 62 CO₂Me

H H H H Me 344 63 CO₂Et

H NH₂ H H Me 427 64 CO₂Et

H H NH₂ H Me 427 65 CO₂Me

H H H H Me 466 66 CO₂Me

H H H H Me 344 67 CO₂Me

H H H H Me 344 68 CO₂Me

H NO₂ H H Me 443 69 CO₂Me

H H NO₂ H Me 443 70 CO₂Et

H H H H i-Pr 400 71 CO₂Me

H NH₂ H H Me 413 72 CO₂Me

H H H H Me 399 73 CO₂Me

H H H H Et 372 74 CO₂Me

H H H H Me 398 75 CO₂Me

H H H H Me 394 76 CO₂Me

H H H H Me 372 77 CO₂Me

H NO₂ H H Me 403 78 CO₂Me

H H NO₂ H Me 403 79 CO₂Me

H H H H Me 394 80 CO₂Me

H NHAc H H Me 455 81 CO₂Me

H H H H Me 488 82 CO₂Me

H NH₂ H H Me 373 83 CO₂Me

H H NH₂ H Me 373 84 CO₂Me

H H H H Me 362 85 CO₂Me

H H H H Me 431 (M + 23) 86 CO₂Me

H H H H Me 380 (M + 23) 87 CO₂Me

H NO₂ H H Me 439 88 CO₂Me

H H NO₂ H Me 439 89 CO₂Me

H H H H Me 430 90 CO₂Me

H NH₂ H H Me 409 91 CO₂Me

H H NH₂ H Me 409 92

H H H H Me 397 93 CN

H H H H Me 325 94 CO₂Me

H H H H NH₂ 359 95 CO₂Me

H H H H NH₂ 395 96 CO₂H

H H H H Me 344 97

H H H H Me 433 98 CN

H H H H Me 361 99

H H H H C₂H₂O₂ 358 100

H H H H C₂H₂O₂ 357 101

Ph H H H H C₂H₂O₂ 314 102

H H H H C₂H₂O₂ 361 103

H H H H C₂H₂O₂ 364 104

H H H H C₂H₂O₂ 342 105 CO₂H

H H H H Me 380 106 CONH₂

H H H H Me 343 107 CONHMe

H H H H Me 357 108 CONMe₂

H H H H Me 371 109

H H H H C₂H₂O₂ 378 110

H H H H C₂H₂O₂ 328 111

H H H H C₂H₂O₂ 356 112

H H H H C₂H₂O₂ 328 113 CO₂Me

H H H H Me 375 114

H H H H C₂H₂O₂ 328 115 CO₂Me

H H H H Me 373 116 CONH₂

H H H H Me 379 117

H H H H C₂H₂O₂ 365 118 CO₂Me

H H H H Me 375 119 CONHMe

H H H H Me 393 120 CONMe₂

H H H H Me 407 121 CO₂Me

H H H H Me 381 122 CO₂Me

H Cl Cl H Me 463 123 CO₂Me

H Cl Cl H Me 427 124 CO₂Me

H H H H Me 381 125 CO₂Et

H H H H Me 408 126 CO₂Me

H Cl Cl H Me 555 127 CO₂Me

Cl H H Cl Me 427 128 CO₂Me

H H H H Me 421 129 CO₂Me

Cl H H Cl Me 558 130 CO₂Me

H H H H Me 345 131 CO₂Et

H Cl Cl H Me 477 132 CO₂Me

H H H H Me 503 133 Ac

H H H H Me 472 134 Ac

H H H H Me 342 135 CO₂Me

H H H H Me 331 136

H H H H Me 527 137

H H H H Me 397 138 CO₂Me

H H H H Me 362 139 CO₂H

H H H H Me 474 140 CO₂H

H H H H Me 344 141 CO₂Me

H H H H Me 346 142 CO₂Me

H H H H Me 380 143 CO₂Me

H H H H Me 486 144 CO₂Me

H H H H Me 436 145 CO₂Me

H H H H Me 518 146

H H H H Me 557 147

H Cl Cl H Me 466 148 CO₂Et —NHPh H H H H Me 359 149 CO₂Me

H H H H Me 360 150 CO₂Me

H H H H Me 504 151

H H H H Me 420 152 C₃H₅O₃

H H H H Me 534 153

H H H H Me 385 154

H H H H Me 373 155

H H NO₂ H Me 574 156 CO₂Me

H Br H H Me 473 157 CO₂Me

H H Br H Me 473 158

H Cl Cl H Me 489 159

H H NO₂ H Me 590 160

H H H H Me 411 161 CO₂Me

H Br H H Me 436 162 CO₂Me

H H Br H Me 438 163 CO₂Me

H Br Br H Me 516 164

H Cl Cl H Me 597 165

H Cl Cl H Me 480 166 CO₂Me

H Br Br H Me 552 167 CO₂Et

H Br Br H Me 530 168 CO₂Me

F H H F Me 540 169 CO₂Me

H H NO₂ H Me 551 170 CO₂Me

H Cl Cl H Me 573 171

H H NO₂ H Me 444 172

H NO₂ H H Me 444 173 CO₂Me

F H H F Me 394 174

F H H F Me 433 175 CO₂Me

H Br Br H Me 548 176 CO₂Me

H H H H Me 355 177 CO₂Me

H NO₂ H H Me 421 178 CO₂Me

H H NO₂ H Me 453 (M + 23) 179 CO₂Me

H Cl Cl H Me 443 180 CN

H H H H Me 341 181 CO₂Me

H H H H Me 598 182 CO₂Me

H Cl Cl H Me 435 183 CO₂Et

H H H H Me 387 184 CO₂Et

H H H H Me 373 185 CO₂Me

H H H H Me 612 186 CO₂Et

H H H H Me 410 187 CO₂Me

H H NO₂ H Me 345 188 CO₂Me

H Cl Cl H Me 668 189 CO₂Me

H H NO₂ H Me 413 190 CO₂H

H Cl Cl H Me 544 191 CN

H H H H Me 565 192 CO₂Me

H Br H H Me 606 (M + 23) 193 CO₂Me

H H Br H Me 584 194 CO₂Et

H H H H Me 373 195 CO₂Et

H H H H Me 427 196 CO₂Et

H Cl Cl H Me 587 197 CO₂Et

H H H H Me 437 198 CO₂Et

H H H H Me 389 199 CO₂Et

H H H H Me 612 200 CO₂Et

H Cl Cl H Me 449 201 CO₂Me

H Cl Cl H Me 450 202 CO₂Me

H Cl Cl H Me 465 203 CO₂Me

H H H H Me 396 204 CO₂Me

H

H H Me 473 205 CO₂Me

H H H H Me 345 206 CO₂Me

H H H H Me 359 207 CO₂Me

H Cl Cl H Me 444 208 CO₂Me

H H H H Me 355 209 CO₂H

H H H H Me 366 210 CO₂Me

H Cl Cl H Me 444 211 CO₂Me

H Cl Cl H Me 430 212 CO₂Me

H H H H Me 416 213 CO₂Me

H Cl Cl H Me 430 214 CO₂Me

H H H H Me 413 215 CO₂Me

H OMe OMe H Me 418 216 CO₂Me

H OMe OMe H Me 454 217 CO₂Me

H H H H Me 362 218 CO₂Me

H

H H Me 445 219 CO₂Me

H H H H Me 359 220 CO₂Me —NHPh H H H H Me 345 221 CO₂Me

H H H H Me 423 222 CO₂Me 2-Pyridyl H H H H Me 353 (M + 23) 223 CO₂Me

H OMe OMe H Me 459 224 CO₂Me

H Cl Cl H Me 485 225 CO₂Me

H H H H Me 345 226 CO₂Me

H H NO₂ H Me 420 227 CO₂Me

H H NO₂ H Me 420 228 CO₂Me

H H H H Me 359 229 CO₂Me

H H H H Me 396 230 CO₂Me

H OH OH H Me 426 231 CO₂Me

H H F H Me 376 232 CO₂Me

H H NO₂ H Me 461 233 CO₂Me

H Cl Cl H Me 468 234 CO₂Me

H H H H Me 373 235 CO₂Me

H H H H Me 375 236 CO₂Me

H NO₂ H H Me 443 237 CO₂Me

H H NO₂ H Me 443 238 CO₂Me

H H H H Me 398 239 CO₂Me

H Cl Cl H Me 491 240 CO₂Me

H

H H Me 509 241 CO₂Me

H H

H Me 473 242 CO₂Me

H H

H Me 509 243 CO₂Me

H H H H Me 310 244 CO₂Me

H

H H Me 524 245 CO₂Me

H H

H Me 488 246 CO₂Me

H H H H Me 308 247 CO₂Me i-Pr H H H H Me 296 248 CO₂Me

H H H H Me 336 249 CO₂Me Me H H H H Me 268 250 CO₂Me

H H

H Me 474 251 CO₂Me

H H

H Me 487 252 CO₂Me N- H H H H Me 339 Morpholino 253 CO₂Me

H H H H Me 337 254 CO₂Me

H H

H Me 488 255 CO₂Me

H

H H Me 474 256 CO₂Me

H

H H Me 456 257 CO₂Me

H

H H Me 431 258 CO₂Me

H

H H Me 500 259 CO₂Me

H

H H Me 499 260 CO₂Me

H

H H Me 481 261 CO₂Me

H H

H Me 500 262 CO₂Me

H H

H Me 499 263 CO₂Me

H H

H Me 431III. Biological Assays and Activity

The assay of phosphodiesterase activity follows the homogeneous SPA(scintillation proximity assay) format under the principle that linearnucleotides preferentially bind yttrium silicate beads in the presenceof zinc sulfate.

In this assay, the enzyme converts radioactively tagged cyclicnucleotides (reaction substrate) to linear nucleotides (reactionproduct) which are selectively captured via ion chelation on ascintillant-containing bead. Radiolabeled product bound to the beadsurface results in energy transfer to the bead scintillant andgeneration of a quantifiable signal. Unbound radiolabel fails to achieveclose proximity to the scintillant and therefore does not generate anysignal.

Specifically, enzyme was diluted in PDE buffer (50 mM pH 7.4 Tris, 8.3mM MgCl₂, 1.7 mM EGTA) with 0.1% ovalbumin such that the finalsignal:noise (enzyme:no enzyme) ratio is 5-10. Substrate (2,8-³H-cAMP or8-³H-cGMP, purchased from Amersham Pharmacia) was diluted in PDE (4, 5,7A) buffer to 1 nCi per gi (or 1 μCi/ml). For each test well, 48 μl ofenzyme was mixed with 4791 substrate and 5 μl test compound (or DMSO) ina white Packard plate, followed by shaking to mix and incubation for 15minutes at room temperature. A 50 μl aliquot of evenly suspended yttriumsilicate SPA beads in zinc sulfate was added to each well to terminatethe reaction and capture the product. The plate was sealed usingTopseal-S (Packard) sheets, and the beads were allowed to settle bygravity for 15-20 minutes prior to counting on a Packard TopCountscintillation counter using a ³H glass program with color quenchcorrection. Output was in color quench-corrected dpm.

Test compounds were diluted in 100% DMSO to a concentration 20× finalassay concentration. DMSO vehicle alone was added to uninhibited controlwells. Inhibition (%) was calculated as follows:Nonspecific binding (NSB)=the mean of CPM of the substrate+buffer+DMSOwellsTotal Binding (TB)=the mean of the enzyme+substrate+DMSO wells${\%\quad{Inhibition}\quad{listed}\quad{in}\quad{Table}\quad 1} = {\left( {1 - \frac{\left( {{{Sample}\quad{CPM}} - {NSB}} \right)}{{TB} - {NSB}}} \right) \times 100}$

The IC₅₀ values were calculated using the Deltagraph 4-parametercurve-fitting program. The IC₅₀ and % Inhibition data on PDE 4, 5, and7A are listed for the indicated compounds in Table 2 below. TABLE 2 Ia

MS IC₅₀ (μM)/% inh. @ μM No. R₁ R₂ R_(3a) R_(3b) R_(3c) R_(3d) R₄(M + 1) PDE7A PDE4 PDE5  6 CO₂H

H H H H Me 360 45% @20 49% @ 5  51 CO₂Me

H H H H Me 358 0.055 0.353 2.7  56 CO₂Et

H H NHAc H Me 445 0.074 0.333 2.5  70 CO₂Et

H H H H i-Pr 400 2.11  73 CO₂Me

H H H H Et 372 1.54 0.998  82 CO₂Me

H NH₂ H H Me 373 0.021 0.204 1.11, 0.864  90 CO₂Me

H NH₂ H H Me 409 0.005 0.237, 0.172 2.33  98 CN

H H H H Me 361 1.13 119 CONHMe

H H H H Me 393 0.658 41% @ 20 133 Ac

H H H H Me 472 1.54 134 Ac

H H H H Me 342 1.14 169 CO₂Me

H H NO₂ H Me 551 0.0053 0.184 170 CO₂Me

H Cl Cl H Me 573 0.0087 0.557 190 CO₂H

H Cl Cl H Me 544 5.9 191 CN

H H H H Me 565 0.593 197 CO₂Et

H H H H Me 437 0.728 69% @ 5 0.362 219 CO₂Me

H H H H Me 359 0.964 61% @ 5 1.1 220 CO₂Me —NHPh H H H H Me 345 0.0841.8 0.637 241 CO₂Me

H H

H Me 473 0.0035 0.954 0.183 242 CO₂Me

H H

H Me 509 0.0038 0.782 0.141 243 CO₂Me

H H H H Me 310 2.6 245 CO₂Me

H H

H Me 488 0.0053 0.875 0.185 248 CO₂Me

H H H H Me 336 0.783 0.171 0.649 250 CO₂Me

H H

H Me 474 0.0074 0.684 2.4 251 CO₂Me

H H

H Me 487 0.0054 0.754 0.26 253 CO₂Me

H H H H Me 337 0.905 0.85 0.303 254 CO₂Me

H H

H Me 488 0.0067 0.664 0.765 261 CO₂Me

H H

H Me 500 0.0063 0.477 0.63 262 CO₂Me

H H

H Me 499 0.008 0.702 3.7

1-37. (canceled)
 38. A method of treating a subject having a disorderameliorated by reducing PDE activity in appropriate cells, whichcomprises administering to the subject a therapeutically effective doseof a compound having the structure;

wherein (a) r₁ is selected from the group consisting of: (i) —COR₅,wherein R₅ is selected from H, optionally substituted C₁₋₈ straight orbranched chain alkyl, optionally substituted aryl and optionallysubstituted arylalkyl; wherein the substituents on the alkyl, aryl andarylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy,halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₂₀R₂₁wherein R₂₀ and R₂₁ are independently selected from the group consistingof hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl,benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form a heterocycleor heteroaryl; (ii) COOR₆, wherein R₆ is selected from H, optionallysubstituted C₁₋₈ straight or branched chain alkyl, optionallysubstituted aryl and optionally substituted arylalkyl; wherein thesubstituents on the alkyl, aryl and arylalkyl group are selected fromC₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy,amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and R₂₁ areindependently selected from the group consisting of hydrogen, C₁₋₈straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl, aryl, orheteroaryl or NR₂₀R₂₁ taken together form a heterocycle or heteroaryl;(iii) cyano; (iv) a lactone or lactam formed with R₄; (v) —CONR₇R₈wherein R₇ and R₈ are independently selected from H, C₁₋₈ straight orbranched chain alkyl, C₃₋₇ cycloalkyl, trifluoromethyl, hydroxy, alkoxy,acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl andheterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl,alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclylgroups may be substituted with carboxyl, alkyl, aryl, substituted aryl,heterocyclyl, substituted heterocyclyl, heteroaryl, substitutedheteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,alkoxy or arylalkyl, or R₇ and R₈ taken together with the nitrogen towhich they are attached form a heterocycle or heteroaryl group; (b) R₂is selected from the group consisting of optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl and optionally substituted C₃₋₇cycloalkyl; (c) R₃ is from one to four groups independently selectedfrom the group consisting of: (i) hydrogen, halo, C₁₋₈ straight orbranched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano,C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro,hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, aryl, heteroaryl, andheterocyclyl; (ii) —NR₁₀R₁₁ wherein R₁₀ and R₁₁ are independentlyselected from H, C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R₁₀ andR₁₁ taken together with the nitrogen form a heteroaryl or heterocyclylgroup; (iii) —NR₁₂COR₁₃ wherein R₁₂ is selected from hydrogen or alkyland R₁₃ is selected from hydrogen, alkyl, substituted alkyl,C₁₋₃alkoxyl, carboxyalkyl, R₃₀R₃₁N(CH₂)_(p)—, R₃₀R₃₁NCO(CH₂)_(p)—, aryl,arylalkyl, heteroaryl and heterocyclyl or R₁₂ and R₁₃ taken togetherwith the carbonyl form a carbonyl containing heterocyclyl group,wherein, R₃₀ and R₃, are independently selected from H, OH, alkyl, andalkoxy, and p is an integer from 1-6, (d) R₄ is selected from the groupconsisting of (i) hydrogen, (ii) C₁₋₃ straight or branched chain alkyl,(iii) benzyl and (iv) —NR₁₃R₁₄ wherein R₁₃ and R₁₄ are independentlyselected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₃alkyl and benzylgroups are optionally substituted with one or more groups selected fromC₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl,C₁₋₈ alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈carboxylate, amino, NR₁₃R₁₄, aryl and heteroaryl; and (e) X is selectedfrom S and O: with the proviso that when R₄ is isopropyl, then R₃ is nothalogen; or comprising administering to the subject a therapeuticallyeffective dose of a compound having the structure;

wherein (a) R₁ is selected from the group consisting of: (i) —COR₅,wherein R₅ is selected from H, optionally substituted C₁₋₈ straight orbranched chain alkyl, optionally substituted aryl and optionallysubstituted arylalkyl; wherein the substituents on the alkyl, aryl andarylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy,halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₂₀R₂₁wherein R₂₀ and R₂₁ are independently selected from the group consistingof hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl,benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form a heterocycleor heteroaryl; (ii) COOR₆, wherein R₆ is selected from H, optionallysubstituted C₁₋₈ straight or branched chain alkyl, optionallysubstituted aryl and optionally substituted arylalkyl; wherein thesubstituents on the alkyl, aryl and arylalkyl group are selected fromC₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy,amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and R₂₁ areindependently selected from the group consisting of hydrogen, C₁₋₈straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl, aryl, orheteroaryl or NR₂₀R₂₁ taken together form a heterocycle or heteroaryl,(i) cyano; (ii) a lactone or lactam formed with R₄; (iii) —CONR₇R₈wherein R₇ and R₈ are independently selected from H C₁₋₈ straight orbranched chain alkyl, C₃₋₇ cycloalkyl, trifluoromethyl, hydroxy, alkoxy,acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl andheterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl,alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclylgroups may be substituted with carboxyl, alkyl, aryl, substituted aryl,heterocyclyl, substituted heterocyclyl, heteroaryl, substitutedheteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,alkoxy or arylalkyl, or R₇ and R₈ taken together with the nitrogen towhich they are attached form a heterocycle or heteroaryl group; (b) R₂is —NR₁₅R₁₆ wherein R₁₅ and R₁₆ are independently selected fromhydrogen, optionally substituted C₁₋₈ straight or branched chain alkyl,arylalkyl, C₃₋₇ cycloalkyl, aryl, heteroaryl, and heterocyclyl or R₁₅and R₁₆ taken together with the nitrogen form a heteroaryl orheterocyclyl group; with the proviso that when R₂ is NHR₁₆, R₁ is not—COOR₆ where R₆ is ethyl; (c) R₃ is from one to four groupsindependently selected from the group consisting of: (i) hydrogen, halo,C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, C₁₋₈alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl,halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, aryl,heteroaryl, and heterocyclyl; (ii) —NR₁₀R₁₁ wherein R₁₀ and R₁₁ areindependently selected from H, C₁₋₈ straight or branched chain alkyl,arylalkyl, C₃₋₇ cycloalkyl, carboxyalkyl, aryl, heteroaryl, andheterocyclyl or R₁₀ and R₁ taken together with the nitrogen form aheteroaryl or heterocyclyl group; (iii) —NR₁₂COR₁₃ wherein R₁₂ isselected from hydrogen or alkyl and R₁₃ is selected from hydrogen,alkyl, substituted alkyl, C₁₋₃alkoxyl, carboxyalkyl, R₃₀R₃₁N(CH₂)_(p)—,R₃₀R₃₁NCO(CH₂)_(p)—, aryl arylalkyl, heteroaryl and heterocyclyl or R₁₂and R₁₃ taken together with the carbonyl form a carbonyl containingheterocyclyl group, wherein, R₃₀ and R₃₁ are independently selected fromH, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein thealkyl group may be substituted with carboxyl, alkyl, aryl, substitutedaryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substitutedheteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,alkoxy or arylalkyl; (d) R₄ is selected from the group consisting of (i)hydrogen, (ii) C₁₋₃ straight or branched chain alkyl, (iii) benzyl and(iv) —NR₁₃R₁₄, wherein R₁₃ and R₁₄ are independently selected fromhydrogen and C₁₋₆ alkyl; wherein the C₁₋₃alkyl and benzyl groups areoptionally substituted with one or more groups selected from C₃₋₇cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₈carboxylate, amino, NR₁₃R₁₄, aryl and heteroaryl; and (e) X is selectedfrom S and O; and the pharmaceutically acceptable salts, esters andpro-drug forms thereof.
 39. A method of preventing a disorderameliorated by reducing PDE activity in appropriate cells in a subject,comprising administering to the subject a prophylactically effectivedose of a compound; having the structure;

wherein (c) R₁ is selected from the group consisting of: (j) —COR₅,wherein R₅ is selected from H, optionally substituted C₁₋₈ straight orbranched chain alkyl, optionally substituted aryl and optionallysubstituted arylalkyl; wherein the substituents on the alkyl, aryl andarylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy,halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₂₀R₂₁wherein R₂₀ and R₂₁ are independently selected from the group consistingof hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl,benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form a heterocycleor heteroaryl; (vi) COOR₆, wherein R₆ is selected from H, optionallysubstituted C₁₋₈ straight or branched chain alkyl, optionallysubstituted aryl and optionally substituted arylalkyl; wherein thesubstituents on the alkyl, aryl and arylalkyl group are selected fromC₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy,amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and R₂₁ areindependently selected from the group consisting of hydrogen, C₁₋₈straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl, aryl, orheteroaryl or NR₂₀R₂₁ taken together form a heterocycle or heteroaryl;(vii) cyano; (viii) a lactone or lactam formed with R₄; (ix) —CONR₇R₈wherein R₇ and R₈ are independently selected from H, C₁₋₈ straight orbranched chain alkyl, C₃₋₇ cycloalkyl, trifluoromethyl, hydroxy, alkoxy,acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl andheterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl,alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclylgroups may be substituted with carboxyl, alkyl, aryl, substituted aryl,heterocyclyl, substituted heterocyclyl, heteroaryl, substitutedheteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,alkoxy or arylalkyl, or R₇ and R₈ taken together with the nitrogen towhich they are attached form a heterocycle or heteroaryl group; (d) R₂is selected from the group consisting of optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl and optionally substituted C₃₋₇cycloalkyl: (c) R₃ is from one to four groups independently selectedfrom the group consisting of: (j) hydrogen, halo, C₁₋₈ straight orbranched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano,C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro,hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, aryl, heteroaryl, andheterocyclyl; (iv) —NR₁₀R₁₁ wherein R₁₀ and R₁₁ are independentlyselected from H, C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R₁₀ andR₁₁ taken together with the nitrogen form a heteroaryl or heterocyclylgroup; (v) —NR₁₂COR₁₃ wherein R₁₂ is selected from hydrogen or alkyl andR₁₃ is selected from hydrogen, alkyl, substituted alkyl, C₁₋₃alkoxyl,carboxyalkyl, R₃₀R₃₁N(CH₂)_(p)—, R₃₀R₃₁NCO(CH₂)_(p)—, aryl, arylalkyl,heteroaryl and heterocyclyl or R₁₂ and R₁₃ taken together with thecarbonyl form a carbonyl containing heterocyclyl group, wherein, R₃₀ andR₃₁ are independently selected from H, OH, alkyl, and alkoxy, and p isan integer from 1-6, (d) R₄ is selected from the group consisting of (i)hydrogen, (ii) C₁₋₃ straight or branched chain alkyl, (iii) benzyl and(iv) —NR₁₃R₁₄, wherein R₁₃ and R₁₄ are independently selected fromhydrogen and C₁₋₆ alkyl; wherein the C₁₋₃alkyl and benzyl groups areoptionally substituted with one or more groups selected from C₃₋₇cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈carboxylate, amino, NR₁₃R₁₄, aryl and heteroaryl; and (e) X is selectedfrom S and O: with the proviso that when R₄ is isopropyl, then R₃ is nothalogen: or comprising administering to the subject a prophylacticallyeffective dose of a compound having the structure;

wherein (b) R₁ is selected from the group consisting of: (j) —COR₅,wherein R₅ is selected from H, optionally substituted C₁₋₈ straight orbranched chain alkyl, optionally substituted aryl and optionallysubstituted arylalkyl; wherein the substituents on the alkyl, aryl andarylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy,halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₂₀R₂₁wherein R₂₀ and R₂₁ are independently selected from the group consistingof hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl,benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form a heterocycleor heteroaryl; (ii) COOR₆, wherein R₆ is selected from H, optionallysubstituted C₁₋₈ straight or branched chain alkyl, optionallysubstituted aryl and optionally substituted arylalkyl; wherein thesubstituents on the alkyl, aryl and arylalkyl group are selected fromC₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy,amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and R₂₁ areindependently selected from the group consisting of hydrogen, C₁₋₈straight or branched chain alkyl, C₃₋₇ cycloalkyl benzyl, aryl, orheteroaryl or NR₂₀R₂₁ taken together form a heterocycle or heteroaryl;(iv) cyano; (v) a lactone or lactam formed with R₄; (vi) —CONR₇R₈wherein R₇ and R₈ are independently selected from H, C₁₋₈ straight orbranched chain alkyl, C₃₋₇ cycloalkyl, trifluoromethyl, hydroxy, alkoxy,acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl andheterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl,alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclylgroups may be substituted with carboxyl, alkyl, aryl, substituted aryl,heterocyclyl, substituted heterocyclyl, heteroaryl, substitutedheteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,alkoxy or arylalkyl, or R₇ and R₈ taken together with the nitrogen towhich they are attached form a heterocycle or heteroaryl group; (b) R₂is —NR₁₅R₁₆ wherein R₁₅ and R₁₆ are independently selected fromhydrogen, optionally substituted C₁₋₈ straight or branched chain alkyl,arylalkyl, C₃₋₇ cycloalkyl, aryl, heteroaryl, and heterocyclyl or R₁₅and R₁₆ taken together with the nitrogen form a heteroaryl orheterocyclyl group; with the proviso that when R₂ is NHR₁₆, R₁ is not—COOR₆ where R₆ is ethyl; (c) R₃ is from one to four groupsindependently selected from the group consisting of: (iii) hydrogen,halo, C₁₋₈ straight or branched chain alkyl, arylalkyl, trifluoromethyl,C₁₋₈ alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈carboxylate, aryl, heteroaryl, and heterocyclyl; (iv) —NR₁₀R₁₁ hereinR₁₀ and R₁₁ are independently selected from H, C₁₋₈ straight or branchedchain alkyl, arylalkyl, C₃₋₇ cycloalkyl, carboxyalkyl, aryl, heteroaryl,and heterocyclyl or R₁₀ and R₁₁ taken together with the nitrogen form aheteroaryl or heterocyclyl group; (iii) —NR₁₂COR₁₃ wherein R₁₂ isselected from hydrogen or alkyl and R₁₃ is selected from hydrogen,alkyl, substituted alkyl, C₁₋₃alkoxyl, carboxyalkyl, R₃₀R₃₁N(CH₂)_(p)—,R₃₀R₃₁NCO(CH₂)_(p)—, aryl, arylalkyl, heteroaryl and heterocyclyl or R₁₂and R₁₃ taken together with the carbonyl form a carbonyl containingheterocyclyl group, wherein, R₃₀ and R₃₁ are independently selected fromH, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein thealkyl group may be substituted with carboxyl, alkyl, aryl, substitutedaryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substitutedheteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,alkoxy or arylalkyl; (di) R₄ is selected from the group consisting of(i) hydrogen, (ii) C₁₋₃ straight or branched chain alkyl, (iii) benzyland (iv) —NR₁₃R₁₄, wherein R₁₃ and R₁₄ are independently selected fromhydrogen and C₁₋₆ alkyl; wherein the C₁₋₃alkyl and benzyl groups areoptionally substituted with one or more groups selected from C₃₋₇cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈carboxylate, amino, NR₁₃R₁₄ aryl and heteroaryl; and (e) X is selectedfrom S and O; and the pharmaceutically acceptable salts, esters andpro-drug forms thereof either preceding or subsequent to an eventanticipated to cause a disorder ameliorated by reducing PDE activity inappropriate cells in the subject.
 40. The method of claim 38 or 39comprising administering to the subject a therapeutically orprophylactically effective dose of a pharmaceutical compositioncomprising a compound of claim 38 and a pharmaceutically acceptablecarrier.
 41. A method of inhibiting PDE activity in a subject, whichcomprises contacting one or more T-cells with a therapeuticallyeffective dose of a compound having the structure;

wherein (e) R₁ is selected from the group consisting of: (k) —COR₅,wherein R₅ is selected from H, optionally substituted C₁₋₈ straight orbranched chain alkyl, optionally substituted aryl and optionallysubstituted arylalkyl; wherein the substituents on the alkyl, aryl andarylalkyl group are selected from C₁₋₁₈ alkoxy, phenylacetyloxy,hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, orNR₂₀R₂₁ wherein R₂₀ and R₂₁ are independently selected from the groupconsisting of hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇cycloalkyl, benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form aheterocycle or heteroaryl; (x) COOR₆, wherein R₆ is selected from H,optionally substituted C₁₋₈ straight or branched chain alkyl, optionallysubstituted aryl and optionally substituted arylalkyl; wherein thesubstituents on the alkyl, aryl and arylalkyl group are selected fromC₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy,amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and R₂₁ areindependently selected from the group consisting of hydrogen, C₁₋₈straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl, aryl, orheteroaryl or NR₂₀R₂₁ taken together form a heterocycle or heteroaryl;(xi) cyano; (xii) a lactone or lactam formed with R₄; (xiii) —CONR₇R₈wherein R₇ and R₈ are independently selected from H, C₁₋₈ straight orbranched chain alkyl, C₃₋₇ cycloalkyl, trifluoromethyl, hydroxy, alkoxy,acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl andheterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl,alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclylgroups may be substituted with carboxyl, alkyl, aryl, substituted aryl,heterocyclyl, substituted heterocyclyl, heteroaryl, substitutedheteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,alkoxy or arylalkyl, or R₇ and R₈ taken together with the nitrogen towhich they are attached form a heterocycle or heteroaryl group; (f) R₂is selected from the group consisting of optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl and optionally substituted C₃₋₇cycloalkyl; (c) R₃ is from one to four groups independently selectedfrom the group consisting of: (k) hydrogen, halo, C₁₋₈ straight orbranched chain alkyl, arylalkyl C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano,C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro,hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, aryl, heteroaryl, andheterocyclyl; (vi) —NR₁₀R₁₁ wherein R₁₀ and R₁₁ are independentlyselected from H, C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R₁₀ andR₁₁ taken together with the nitrogen form a heteroaryl or heterocyclylgroup; (vii) —NR₁₂COR₁₃ wherein R₁₂ is selected from hydrogen or alkyland R₁₃ is selected from hydrogen, alkyl, substituted alkyl,C₁₋₃alkoxyl, carboxyalkyl, R₃₀R₃₁N(CH₂)_(p)—, R₃₀R₃₁NCO(CH₂)_(p)—, aryl,arylalkyl, heteroaryl and heterocyclyl or R₁₂ and R₁₃ taken togetherwith the carbonyl form a carbonyl containing heterocyclyl group,wherein, R₃₀ and R₃₁ are independently selected from H, OH, alkyl, andalkoxy, and p is an integer from 1-6, (d) R₄ is selected from the groupconsisting of (i) hydrogen, (ii) C₁₋₃ straight or branched chain alkyl,(iii) benzyl and (iv) —NR₁₃R₁₄, wherein R₁₃ and R₁₄ are independentlyselected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₃alkyl and benzylgroups are optionally substituted with one or more groups selected fromC₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl,C₁₋₈ alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈carboxylate, amino, NR₁₃R₁₄, aryl and heteroaryl; and (e) X is selectedfrom S and O; with the proviso that when R₄ is isopropyl, then R₃ is nothalogen, or which comprises contacting one or more T-cells with atherapeutically effective dose of a compound having the structure:

wherein (c) R₁ is selected from the group consisting of: (k) —COR₅,wherein R₅ is selected from H, optionally substituted C₁₋₈ straight orbranched chain alkyl, optionally substituted aryl and optionallysubstituted arylalkyl; wherein the substituents on the alkyl, aryl andarylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy,halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₂₀R₂₁wherein R₂₀ and R₂₁ are independently selected from the group consistingof hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl,benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form a heterocycleor heteroaryl, (ii) COOR₆, wherein R₆ is selected from H, optionallysubstituted C₁₋₈ straight or branched chain alkyl, optionallysubstituted aryl and optionally substituted arylalkyl; wherein thesubstituents on the alkyl, aryl and arylalkyl group are selected fromC₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy,amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and R₂₁ areindependently selected from the group consisting of hydrogen, C₁₋₈straight or branched chain alkyl, C₃₋₇ cyloalky benzyl, aryl, orheteroaryl or NR₂₀R₂₁ taken together form a heterocycle or heteroaryl;(vii) cyano; (viii) a lactone or lactam formed with R₄; (ix) —CONR₇R₈wherein R₇ and R₈ are independently selected from H, C₁₋₈ straight orbranched chain alkyl, C₃₋₇ cycloalkyl, trifluoromethyl, hydroxy, alkoxy,acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl andheterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl,alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclylgroups may be substituted with carboxyl, alkyl, aryl, substituted aryl,heterocyclyl, substituted heterocyclyl, heteroaryl, substitutedheteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,alkoxy or arylalkyl, or R₇ and R₈ taken together with the nitrogen towhich they are attached form a heterocycle or heteroaryl group; (b) R₂is —NR₁₅R₁₆ wherein R₁₅ and R₁₆ are independently selected fromhydrogen, optionally substituted C₁₋₈ straight or branched chain alkyl,arylalkyl, C₃₋₇ cycloalkyl, aryl, heteroaryl, and heterocyclyl or R₁₅and R₁₆ taken together with the nitrogen form a heteroaryl orheterocyclyl group; with the proviso that when R₂ is NHR₁₆, R₁ is not—COOR₆ where R₆ is ethyl; (c) R₃ is from one to four groupsindependently selected from the group consisting of: (v) hydrogen, halo,C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, C₁₋₈alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl,halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, aryl,heteroaryl, and heterocyclyl; (vi) —NR₁₀R₁₁ wherein R₁₀ and R₁₁ areindependently selected from H, C₁₋₈ straight or branched chain alkyl,arylalkyl, C₃₋₇ cycloalkyl, carboxyalkyl, aryl, heteroaryl, andheterocyclyl or R₁₀ and R₁₁ taken together with the nitrogen form aheteroaryl or heterocyclyl group; (iii) —NR₁₂COR₁₃ wherein R₁₂ isselected from hydrogen or alkyl and R₁₃ is selected from hydrogen,alkyl, substituted alkyl, C₁₋₃alkoxyl, carboxyalkyl, R₃₀R₃₁N(CH₂)_(p)—,R₃₀R₃₁NCO(CH₂)_(p)—, aryl, arylalkyl, heteroaryl and heterocyclyl or R₁₂and R₁₃ taken together with the carbonyl form a carbonyl containingheterocyclyl group, wherein, R₃₀ and R₃₁ are independently selected fromH, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein thealkyl group may be substituted with carboxyl, alkyl, aryl, substitutedaryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substitutedheteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,alkoxy or arylalkyl; (dii) R₄ is selected from the group consisting of(i) hydrogen, (ii) C₁₋₃ straight or branched chain alkyl, (iii) benzyland (iv) —NR₁₃R₁₄, wherein R₁₃ and R₁₄ are independently selected fromhydrogen and C₁₋₆ alkyl; wherein the C₁₋₃alkyl and benzyl groups areoptionally substituted with one or more groups selected from C₃₋₇cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈carboxylate, amino, NR₁₃R₁₄, aryl and heteroaryl; and (e) X is selectedfrom S and O; and the pharmaceutically acceptable salts, esters andpro-drug forms thereof.
 42. The method of claim 38, 39 or 41, whereinthe disorder is selected from the group consisting of transplant-relateddisorders, inflammatory-related disorders, AIDS-related disorders,vascular diseases, and erectile dysfunction.
 43. The method of claim 38,wherein the disorder is selected from the group consisting ofhypersensitivity, allergy, arthritis, asthma, bee sting, animal bite,bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor,a urinary tract disorder, inflammatory bowel disease, stroke, erectiledysfunction, HIV/AIDS, cardiovascular disease, gastrointestinal motilitydisorder, and psoriasis.
 44. A method of artificially modifying ananimal, comprising administering to the animal's T-cells a compoundhaving the structure;

wherein (g) R₁ is selected from the group consisting of: (l)—COR₅,wherein R₅ is selected from H, optionally substituted C₁₋₈ straight orbranched chain alkyl, optionally substituted aryl and optionallysubstituted arylalkyl; wherein the substituents on the alkyl, aryl andarylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy,halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₂₀R₂₁wherein R₂₀ and R₂₁ are independently selected from the group consistingof hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl,benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form a heterocycleor heteroaryl; (xiv) COOR₆, wherein R₆ is selected from H, optionallysubstituted C₁₋₈ straight or branched chain alkyl, optionallysubstituted aryl and optionally substituted arylalkyl; wherein thesubstituents on the alkyl, aryl and arylalkyl group are selected fromC₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy,amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and R₂₁ areindependently selected from the group consisting of hydrogen, C₁₋₈straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl, aryl, orheteroaryl or NR₂₀R₂₁ taken together form a heterocycle or heteroaryl;(xv) cyano; (xvi) a lactone or lactam formed with R₄; (xvii) —CONR₇R₈wherein R₇ and R₈ are independently selected from H, C₁₋₈ straight orbranched chain alkyl, C₃₋₇ cycloalkyl, trifluoromethyl, hydroxy, alkoxy,acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl andheterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl,alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclylgroups may be substituted with carboxyl, alkyl, aryl, substituted aryl,heterocyclyl, substituted heterocyclyl, heteroaryl, substitutedheteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,alkoxy or arylalkyl, or R₇ and R₈ taken together with the nitrogen towhich they are attached form a heterocycle or heteroaryl group; (h) R₂is selected from the group consisting of optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl and optionally substituted C₃₋₇cycloalkyl: (c) R₃ is from one to four groups independently selectedfrom the group consisting of: (l) hydrogen, halo, C₁₋₈ straight orbranched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano,C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro,hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, aryl, heteroaryl, andheterocyclyl; (viii) —NR₁₀R₁₁ wherein R₁₀ and R₁₁ are independentlyselected from H, C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R₁₀ andR₁₁ taken together with the nitrogen form a heteroaryl or heterocyclylgroup; (ix) —NR₁₂COR₁₃ wherein R₁₂ is selected from hydrogen or alkyland R₁₃ is selected from hydrogen, alkyl, substituted alkyl,C₁₋₃alkoxyl, carboxyalkyl, R₃₀R₃₁N(CH₂)_(p)—, R₃₀R₃₁NCO(CH₂)_(p)—, aryl,arylalkyl, heteroaryl and heterocyclyl or R₁₂ and R₁₃ taken togetherwith the carbonyl form a carbonyl containing heterocyclyl group,wherein, R₃₀ and R₃₁ are independently selected from H, OH, alkyl, andalkoxy, and p is an integer from 1-6, (d) R₄ is selected from the groupconsisting of (i) hydrogen, (ii) C₁₋₃ straight or branched chain alkyl,(iii) benzyl and (iv) —NR₁₃R₁₄, wherein l₁₃ and R₁₄ are independentlyselected from hydrogen and C₁₋₆ alkyl; wherein the C₁₋₃alkyl and benzylgroups are optionally substituted with one or more groups selected fromC₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl,C₁₋₈ alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈carboxylate, amino, NR₁₃R₁₄, aryl and heteroaryl; and (e) X is selectedfrom S and O; with the proviso that when R₄ is isopropyl, then R₃ is nothalogen: or comprising administering to the animal's T-cells a compoundhaving the structure;

wherein (d) R₁ is selected from the group consisting of: (l) —COR₅,wherein R₅ is selected from H, optionally substituted C₁₋₈ straight orbranched chain alkyl, optionally substituted aryl and optionallysubstituted arylalkyl; wherein the substituents on the alkyl, aryl andarylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy,halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₂₀R₂₁wherein R₂₀ and R₂₁ are independently selected from the group consistingof hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl,benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form a heterocycleor heteroaryl; (ii) COOR₆, wherein R₆ is selected from H, optionallysubstitute C₁₋₈ straight or branched chain alkyl, optionally substitutedaryl and optionally substituted arylalkyl; wherein the substituents onthe alkyl, aryl and arylalkyl group are selected from C₁₋₈ alkoxy,phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano,carboalkoxy, or NR₂₀R₂, wherein R₂₀ and R₂₁ are independently selectedfrom the group consisting of hydrogen, C₁₋₃ straight or branched chainalkyl, C₃₋₇ cycloalkyl benzyl, aryl, or heteroaryl or NR₂₀R₂₁ takentogether form a heterocycle or heteroaryl; (x) cyano; (xi) a lactone orlactam formed with R₄; (xii) —CONR₇R₈ wherein R₇ and R₈ areindependently selected from H, C₁₋₈ straight or branched chain alkyl,C₃₋₇ cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl,carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; wherein thealkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl,aryl, heteroaryl and heterocyclyl groups may be substituted withcarboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substitutedheterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid,sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl, or R₇ and R₈taken together with the nitrogen to which they are attached form aheterocycle or heteroaryl group; (b) R₂ is —NR₁₅R₁₆ wherein R₁₅ and R₁₆are independently selected from hydrogen, optionally substituted C₁₋₈straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, aryl,heteroaryl, and heterocyclyl or R₁₅ and R₁₆ taken together with thenitrogen form a heteroaryl or heterocyclyl group; with the proviso thatwhen R₂ is NHR₁₆, R₁ is not —COOR₆ where R₆ is ethyl; (c) R₃ is from oneto four groups independently selected from the group consisting of:(vii) hydrogen, halo, C₁₋₈ straight or branched chain alkyl, arylalkyl,C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl,C₁₋₈ alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈carboxylate, aryl, heteroaryl, and heterocyclyl; (viii) —NR₁₀R₁₁ whereinR₁₀ and R₁₁ are independently selected from H, C₁₋₈ straight or branchedchain alkyl, arylalkyl, C₃₋₇ cycloalkyl, carboxyalkyl, aryl, heteroaryl,and heterocyclyl or R₁₀ and R₁₁ taken together with the nitrogen form aheteroaryl or heterocyclyl group; (iii) —NR₁₂COR₁₃ wherein R₁₂ isselected from hydrogen or alkyl and R₁₃ is selected from hydrogen,alkyl, substituted alkyl, C₁₋₃alkoxyl, carboxyalkyl, R₃₀R₃₁N(CH₂)_(p)—,R₃₀R₃₁NCO(CH₂)_(p)—, aryl, arylalkyl, heteroaryl and heterocyclyl or R₁₂and R₁₃ taken together with the carbonyl form a carbonyl containingheterocyclyl group, wherein, R₃₀ and R₃₁ are independently selected fromH, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein thealkyl group may be substituted with carboxyl, alkyl, aryl, substitutedaryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substitutedheteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,alkoxy or arylalkyl; (diii) R₄ is selected from the group consisting of(i) hydrogen, (ii) C₁₋₃ straight or branched chain alkyl, (iii) benzyland (iv) —NR₁₃R₁₄, wherein R₁₃ and R₁₄ are independently selected fromhydrogen and C₁₋₆ alkyl; wherein the C₁₋₃alkyl and benzyl groups areoptionally substituted with one or more groups selected from C₃₋₇cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈carboxylate, amino, NR₁₃R₁₄, aryl and heteroaryl; and (e) X is selectedfrom S and O; and the pharmaceutically acceptable salts, esters andpro-drug forms thereof.
 45. A method of claim 44 wherein the animal is amammal.
 46. A method of claim 45 wherein the animal is selected from thegroup consisting of mouse, rat, rabbit, and guinea pig.
 47. A method oftreating a subject having a disorder ameliorated by reducing PDEactivity in appropriate cells, which comprises administering to thesubject a therapeutically effective dose of a compound having thestructure of Formula I wherein R₄ is C₁₋₈ straight or branched chainalkyl and X is O.